NMR-Based Metabolomics for the Assessment of Inhaled Pharmacotherapy in Chronic Obstructive Pulmonary Disease Patients.

The aim of this proof-of-concept, pilot study was the evaluation of the effects of steroid administration and suspension of an inhaled corticosteroid (ICS)-long-acting ß2-agonist (LABA) extrafine fixed dose combination (FDC) on metabolomic fingerprints in subjects with chronic obstructive pulmonary disease (COPD). We hypothesized that a comprehensive metabolomics approach discriminates across inhaled pharmacotherapies and that their effects on metabolomic signatures depend on the biological fluids analyzed. We performed metabolomics via nuclear magnetic resonance (NMR) spectroscopy in exhaled breath condensate (EBC), sputum supernatants, serum, and urine. Fourteen patients suffering from COPD who were on regular inhaled fluticasone propionate/salmeterol therapy (visit 1) were consecutively treated with 2-week beclomethasone dipropionate/formoterol (visit 2), 4-week formoterol alone (visit 3), and 4-week beclomethasone/formoterol (visit 4). The comprehensive NMR-based metabolomics approach showed differences across all pharmacotherapies and that different biofluids provided orthogonal information. Serum formate was lower at visits 1 versus 3 (P = 0.03), EBC formate was higher at visit 1 versus 4 (P = 0.03), and urinary 1-methyl-nicotinamide was lower at 3 versus 4 visit (P = 0.002). NMR-based metabolomics of different biofluids distinguishes across inhaled pharmacotherapies, provides complementary information on the effects of an extrafine ICS/LABA FDC on metabolic fingerprints in COPD patients, and might be useful for elucidating the ICS mechanism of action.

Respiratory Needs in Patients with Type 1 Spinal Muscular Atrophy Treated with Nusinersen.

OBJECTIVE: To evaluate the effects of nusinersen on respiratory function of patients with type 1 spinal muscular atrophy. STUDY DESIGN: Observational, longitudinal cohort study. We collected respiratory data from 118 children with type 1 spinal muscular atrophy and differing pulmonary requirements and conducted a semistructured qualitative interview among a subsample of caregivers at baseline, 6 months, and 10 months after the first nusinersen treatment. Patients were stratified according to ventilation modalities and age at study entry. RESULTS: Most patients in our cohort remained stable (84/109 = 77%). More than 80% of the children treated before age 2 years survived, in contrast to the lower survival reported in natural history studies, and did so without tracheostomy or noninvasive ventilation (NIV) ≥16 hours. In those less than 2 years old, only 3 patients shifted from NIV ≤10 hours to NIV >10 hours, and the other 3 reduced the hours of NIV required. Most of the older patients remained stable; this included not only those on tracheostomy or NIV >10 hours but also 75% of those on NIV ≤10 hours. CONCLUSIONS: Our results suggest that nusinersen may produce some improvement in the progression of respiratory impairment, both in terms of survival and need for respiratory support ≥16 hours, especially before the age of 2 years.

Brain regions and functional interactions supporting early word recognition in the face of input variability.

Perception and cognition in infants have been traditionally investigated using habituation paradigms, assuming that babies' memories in laboratory contexts are best constructed after numerous repetitions of the very same stimulus in the absence of interference. A crucial, yet open, question regards how babies deal with stimuli experienced in a fashion similar to everyday learning situations-namely, in the presence of interfering stimuli. To address this question, we used functional near-infrared spectroscopy to test 40 healthy newborns on their ability to encode words presented in concomitance with other words. The results evidenced a habituation-like hemodynamic response during encoding in the left-frontal region, which was associated with a progressive decrement of the functional connections between this region and the left-temporal, right-temporal, and right-parietal regions. In a recognition test phase, a characteristic neural signature of recognition recruited first the right-frontal region and subsequently the right-parietal ones. Connections originating from the right-temporal regions to these areas emerged when newborns listened to the familiar word in the test phase. These findings suggest a neural specialization at birth characterized by the lateralization of memory functions: the interplay between temporal and left-frontal regions during encoding and between temporo-parietal and right-frontal regions during recognition of speech sounds. Most critically, the results show that newborns are capable of retaining the sound of specific words despite hearing other stimuli during encoding. Thus, habituation designs that include various items may be as effective for studying early memory as repeated presentation of a single word.

Newborns are sensitive to multiple cues for word segmentation in continuous speech.

Before infants can learn words, they must identify those words in continuous speech. Yet, the speech signal lacks obvious boundary markers, which poses a potential problem for language acquisition (Swingley, Philos Trans R Soc Lond. Series B, Biol Sci 364(1536), 3617-3632, 2009). By the middle of the first year, infants seem to have solved this problem (Bergelson & Swingley, Proc Natl Acad Sci 109(9), 3253-3258, 2012; Jusczyk & Aslin, Cogn Psychol 29, 1-23, 1995), but it is unknown if segmentation abilities are present from birth, or if they only emerge after sufficient language exposure and/or brain maturation. Here, in two independent experiments, we looked at two cues known to be crucial for the segmentation of human speech: the computation of statistical co-occurrences between syllables and the use of the language's prosody. After a brief familiarization of about 3 min with continuous speech, using functional near-infrared spectroscopy, neonates showed differential brain responses on a recognition test to words that violated either the statistical (Experiment 1) or prosodic (Experiment 2) boundaries of the familiarization, compared to words that conformed to those boundaries. Importantly, word recognition in Experiment 2 occurred even in the absence of prosodic information at test, meaning that newborns encoded the phonological content independently of its prosody. These data indicate that humans are born with operational language processing and memory capacities and can use at least two types of cues to segment otherwise continuous speech, a key first step in language acquisition.

On the edge of language acquisition: inherent constraints on encoding multisyllabic sequences in the neonate brain.

To understand language, humans must encode information from rapid, sequential streams of syllables - tracking their order and organizing them into words, phrases, and sentences. We used Near-Infrared Spectroscopy (NIRS) to determine whether human neonates are born with the capacity to track the positions of syllables in multisyllabic sequences. After familiarization with a six-syllable sequence, the neonate brain responded to the change (as shown by an increase in oxy-hemoglobin) when the two edge syllables switched positions but not when two middle syllables switched positions (Experiment 1), indicating that they encoded the syllables at the edges of sequences better than those in the middle. Moreover, when a 25 ms pause was inserted between the middle syllables as a segmentation cue, neonates' brains were sensitive to the change (Experiment 2), indicating that subtle cues in speech can signal a boundary, with enhanced encoding of the syllables located at the edges of that boundary. These findings suggest that neonates' brains can encode information from multisyllabic sequences and that this encoding is constrained. Moreover, subtle segmentation cues in a sequence of syllables provide a mechanism with which to accurately encode positional information from longer sequences. Tracking the order of syllables is necessary to understand language and our results suggest that the foundations for this encoding are present at birth.

Newborn's brain activity signals the origin of word memories.

Recent research has shown that specific areas of the human brain are activated by speech from the time of birth. However, it is currently unknown whether newborns' brains also encode and remember the sounds of words when processing speech. The present study investigates the type of information that newborns retain when they hear words and the brain structures that support word-sound recognition. Forty-four healthy newborns were tested with the functional near-infrared spectroscopy method to establish their ability to memorize the sound of a word and distinguish it from a phonetically similar one, 2 min after encoding. Right frontal regions--comparable to those activated in adults during retrieval of verbal material--showed a characteristic neural signature of recognition when newborns listened to a test word that had the same vowel of a previously heard word. In contrast, a characteristic novelty response was found when a test word had different vowels than the familiar word, despite having the same consonants. These results indicate that the information carried by vowels is better recognized by newborns than the information carried by consonants. Moreover, these data suggest that right frontal areas may support the recognition of speech sequences from the very first stages of language acquisition.

TRITRIAL: The Impact of Fixed Triple Therapy with Beclometasone/Formoterol/Glycopyrronium on Health Status and Adherence in Chronic Obstructive Pulmonary Disease in an Italian Context of Real Life.

Purpose: The TRITRIAL study assessed the effects of beclometasone dipropionate/formoterol fumarate/glycopyrronium (BDP/FF/G) fixed combination in patients with chronic obstructive pulmonary disease (COPD) in a real-world setting, focusing on patient's experience and perspective through the use of patients reported outcomes. Patients and Methods: TRITRIAL was a multicenter, prospective, observational study conducted on patients with moderate-severe COPD treated with BDP/FF/G fixed therapy for 12 months. The main objective was to evaluate the impact of BDP/FF/G on health status through the COPD Assessment Test (CAT) score. Additional assessments included adherence and satisfaction, measured by the TAI-10/12 questionnaire and a specifically designed eight-item questionnaire, quality of life through the EQ-5D-5L test, sleep quality through the COPD and Asthma Sleep Impact Scale (CASIS), as well as safety and disease-related outcomes. Results: Data from 655 patients were analyzed in the study. The mean total CAT score significantly improved (from 22.8 at baseline to 18.1 at 6 months and 16.5 at 12 months; p < 0.0001), as well as all the eight CAT sub-items, which decreased on average by 0.5-0.9 points during the study. Adherence and usability of the inhaler also improved during the study, with a decrease in poor compliance (from 30.1% to 18.3%) and an increase in good compliance (from 51.8% to 58.3%) according to the TAI score. Patients also benefited from significantly improved quality of life (EQ Index from 0.70 to 0.80; EQ-5D VAS score from 55.1 to 63.1) and sleep quality (CASIS score from 41.1 to 31.8). Finally, patients reported a significant reduction in exacerbation during the study. Conclusion: TRITRIAL showed that the BDP/FF/G fixed combination is effective and safe in patients with moderate-severe COPD and poorly controlled disease, improving patients' HRQoL, sleep quality, adherence and inhaler usability and reducing COPD symptoms and the risk of exacerbation in a real-life setting.

Cause-specific mortality of very preterm infants and antenatal events.

OBJECTIVE: To assess the relationship between antenatal factors and cause-specific risk of death in a large area-based cohort of very preterm infants. STUDY DESIGN: The ACTION (Accesso alle Cure e Terapie Intensive Ostetriche e Neonatali) study recruited during an 18-month period all infants 22-31 weeks' gestational age admitted to neonatal care in 6 Italian regions (n=3040). We analyzed the data of 2974 babies without lethal or acutely life-threatening malformations. Cause-specific risks of death adjusted for competing causes were calculated, and region-stratified multiple Cox regression analyses were used to study the association between cause-specific mortality and infants' characteristics, pregnancy complications, antenatal steroids, and place of birth. RESULTS: Deaths attributable to respiratory problems and intraventricular hemorrhage prevailed in the first 2 weeks of life, and those attributable to infections and gastrointestinal diseases afterwards. Antepartum hemorrhage was associated with respiratory deaths (hazard ratio [HR] 1.6, 95% CI 1.1-2.4), and maternal infection with deaths attributable to asphyxia (HR 32.5, 95% CI 4.1-259.4) and to respiratory problems (HR 2.8, 95% CI 1.6-5.2). Preterm premature rupture of membranes increased the likelihood of deaths due to neonatal infection (HR 1.8, 95% CI 1.0-3.1), and preterm labor/contractions of those due to respiratory (HR 1.5, 95% CI 1.1-2.0) and gastrointestinal diseases (HR 5.8, 95% CI 2.1-16.3). In addition, a birth weight z-score<-1 was associated with increasing hazards of death resulting from asphyxia, late infections, respiratory, and gastrointestinal diseases. CONCLUSIONS: Different complications of pregnancy lead to different cause-specific mortality patterns in very preterm infants.

Pregnancy disorders leading to very preterm birth influence neonatal outcomes: results of the population-based ACTION cohort study.

BACKGROUND: We examined the relationships between -pregnancy disorders leading to very preterm birth -(spontaneous preterm labor, prelabor premature rupture of -membranes (PPROM), hypertension/preeclampsia, -intrauterine growth restriction (IUGR), antenatal hemorrhage, and maternal -infection), both in isolation and grouped together as -"disorders of placentation" (hypertensive disorders and IUGR) vs. -"presumed infection/inflammation" (all the others), and several unfavorable neonatal outcomes. METHODS: We examined a population-based prospective cohort of 2,085 singleton infants of 23-31 wk gestational age (GA) born in six Italian regions (the Accesso alle Cure e Terapie Intensive Ostetriche e Neonatali (ACTION) study). RESULTS: Neonates born following disorders of placentation had a higher GA and better overall outcomes than those born following infection/inflammation. After adjustment for GA, however, they showed higher risk of mortality (odds ratio, OR: 1.4; 95% confidence interval, CI: 1.0-2.0), bronchopulmonary dysplasia (BPD) (OR: 2.5; CI: 1.8-3.6), and retinopathy of prematurity (ROP) (OR: 2.0; CI: 1.1-3.5), especially in growth-restricted infants, and a lower risk of intraventricular hemorrhage (IVH) (OR: 0.5; CI: 0.3-0.8) and periventricular leukomalacia (PVL) (OR: 0.6; CI: 0.4-1.1) as compared with infants born following -infection/inflammation disorders. CONCLUSION: Our data confirm the hypothesis that, in very preterm infants, adverse outcomes are both a function of immaturity (low GA) and of complications leading to preterm birth. The profile of risk is different in different pregnancy disorders.